Synthesis of thiolactones



Patented Aug. 22, 1950 2,519,720 SYNTHESIS F THIOLACTONES Joseph DonaldSurmatis, Nutley, and Walter Kimel, Highland Park, N. J assignors toHofimann-La Roche Inc., Nutley, N. J., a corpora- 7 tion of New JerseyNo Drawing. Application December 22, 1948,

Serial No. 66,846

The present invention relates to a new method for preparing 3,4-(2'-keto-irnidazolido) thiophanes which can be characterized by the followingformula:

In the above formula, R and R stand for aralkyl radicals, as forexample, a-aralkyl radicals like benzyl and 04- or ring substitutedbenzyl, for example, a-methyland e-ethyl-benzyl, o-methyl-. benzyl,p-ethyl-benzyl, p-methoxy-benzyl, or pethoxy-benzyl. The compounds asrepresented by the above formula are valuable intermediates for thesynthesis of biotin and are disclosed in the Goldberg and Sternbachapplications, Serial Nos. 673,642, filed May 31, 1946, now Patent No.2,489,232, and 761,444, filed July 16, 1947, now Patent 2,489,234. Theprocess for preparing the compounds as revealed in the aforementionedapplications involves a three-step procedure as follows:

l. A 3,4-(2 keto-imidazolido) -2-keto-5-acyloxy-tetrahydrofuran of thegeneral Formula B, or the corresponding free aldehydo-acid (C) or-itscyclic form (D) in which R and R. have the same significance as 8Claims. (01. 26 0--3 09) of an alkali metal hydrosulfide, such as slumhydrosulfide.

3. The reaction mixture obtained in step/2 is acidified in the cold,extracted with ether, the, ether extract concentrated in vacuo and theresidue reduced with zinc and acetic acid, the reduced reaction mixturefiltered, the filtrate concentrated in vacuo, the residue extracted withether and the ether solution concentrated, the thiolactone of Formula Acrystallizing out P le $2 after about 20-60 hours.

According to the present, invention, we have now found that thethiolactones can be produced by a new and simplified procedure involvinges-' sentially two steps.

(1) Reacting the 3,4-(2'-keto-imidazolido)2-keto-5-acyloxy-tetrahydrofuran of Formula B, or the corresponding freealdehydo-acid (C) or its cyclic form (D) in a solution of an alkalimetal hydrosulfide, such as sodium, potassium or lithium hydrosulfide,inanaqueous medium, such as water or a mixtureof alcohol and-water,preferably bystirring at. reflux temperature. It is advantageous toemploy an aqueous-alcohol solution, since larger yields areobtainedthereby. The alcohol may ,be'a lower aliphatic alcohol such asmethyl, ethyl, propyl, and the like. The ratio of alcohol to water mayvary over wide limits, as for example, from approximately 25% to 5%:95%. It is preferable to employ I an approximately, 50 per centalcohol'soluti on,

since greatest yields are obtained thereby. (2) Reducing the reactionproduct obtained from step 1) with nascent hydrogen, as for example,obtained from zinc with an acid, suchas acetic acid, or preferably fromzinc with dilute hydrochloric acid, since yields obtained were highestwhen the combination of-zinc and hydrochloric acid were employed as thereducing agent. Other metals, such as iron, and other, acids such assulfuric, phosphoric, formic and, propionic acids may be employed toproduce the nascent hydrogen. H I

It was found advantageous to treat the reaction product obtained by step(1) prior to step (2) by acidifyingit with an acid such as sulfuric orhydrochloric acid, and extracting the reaction product with an inertsolvent, such as benzene, toluene, or other hydrocarbon solvents. Theacid also decomposes the excess alkali metal hydrosulfide, the hydrogensulfide formed being swept out of the reaction vessel.

Thus it will be 's-e'enthat applicants proces eliminates the use ofhydrogen sulfide in combination with hydrogen chloride heretofore re-'quired and the sub-zero temperatures employed in the previous procedure.Further, the new procedure considerably reduces the time required forproducing the thiolactone. In addition, the thiolactone obtained by thenew pro cedure is'of such purity that canbe employed directly in thesynthesis of biotin without further purification.

The following examples will serve to illustrate the invention.

Example 1 In a reaction vessel provided with a stirrer,

condenser, and a thermometer,. there. were placed 16 liters of 50 percent alcohol-water solution, 3,000 grams of sodium hydrosulfide (NaHS)and 1,000 grams of 3,4-(1',3-dibenzyl-2--l eto-imidazolido)-2-keto-5-acetoxy-tetrahydrofuran, which hereinafter for the sake ofbrevity is referred t as the cycloacetate.

The. mi ture was stirred a 3.0-3. 0.. for one hour, during which time itdissolvedto give a green lored solution... The solution was. thenstirred; a reflux temperature. for hours. It was hen allowe to coolat'2.5. Q. y tanding tor .6 hours.

Four ter of. benz e were added. and conce trat d" hy rochlori acid wasdropped in. from. a eparatory tu nel wh estir ing until he olution wastrongly a d."- A. total f. 3500 cc. of hydrochloric acid was required.The benzene layer was epa a ed. wa hed. twice. with. an. equ vo ume ofate and oncentrated to a syr p nde acuum.

' All the syrupy product was dissolved in. seven liters, of. glacialacetic. acid, and treated with 3; kg. oiling dust, The reaction mixturewas stirred for 16' hours at C. then for two hours at refluxtemperature.The zinc was filtered off and washedifirst with acetic acid andthen withwarm benzene. The filtrates were combined and distilled" to a syrupunder vacuo.

To the residue wereaddedl liters of benzene, and-then 3' liters ofconcentrated hydrochloric acid were; addedin-- minutes. The stirring wascontinued for an additional 30 minutes. The benzene layer was separatedand washed two times with an equal volume ofwater. On concentrationunder vacuum with a hot water bath, a solid crystalline mass'wasobtained in the 'fiask and was washed with ether. Inth-is manner, 3,4

( l-" ,3" dibenzyl-Z"-keto imidazolido) -thiop-hane In a reaction vesselfitted with a stirrer, cone denser and thermometer, there were placedone liter of a per cent-'alcohol-water solution, 300 grams of sodiumhydrosulfide, and 109 grams of thecycloacetate. The reaction mixture wasstirred for one hour -at30:3.5 6., giving a. green solution. This wasthen stirred atreflux temperature'for six hours and cooled-to 2590. byallowing to stand for 16 hours. .590: cc.of benzene were then added andconcentrated hydrochloric acid was. dropped in from the-separatoryfunnel until the aqueous layer was. stronglyacid. The benzene layer was.separated, washedtw-ice with water and'concentrated: to a syrup u dervacuum.

The syrup: was dissolved. H1700 cc. of;- glacial acetic acid. To thiswere: added 30.0 grams of zinc dust and the: reaction mixture wasstirred for 16 hours at 25 (2..., then refluxed, for one hour. The zincwas filtered oil and washed well with acetic acidaand finallywitlr warmbenzene. The solvents werev combined and distill d tea light syrup. Oneliter of benzene was added to the syrup and then 300 cc. of concentratedhydrochloric acid were dropped in while stirring in 30 minutes. Thestirring was then continued for another 30 minutes. The benzene layerwas separated, washed with water and concentrated under Vacuum. A solidmass of white crystals was obtained. The crystals were dissolved inmethyl alcohol and ether was then added to the Solution to. inducecrystallization. There was thus obtained3,4-(l',3'-dibenzyl-2-keto-imida- 'zolido) -thiophane in. a yield ofabout 52 per cent of theory.

By comparing Example 2 with Example 1, it will be seen that a greateryield of the thiolactone obtained, even when the volume of the alcohol--water solution is considerably reduced. This is of considerableadvantage, since it permits product-ion of larger batches in reactionvessels of the same size.

Exampl -3.

grams of the cycloacetate, 300 grams of. sodium hydrosulfide and 1,000cc. -of a 50 per cent alcohol-water solution were stirred for one hourat 30-35" C., then at reflux temperature for 6 hours. 500 cc. of benzenewere added and hydrochloric acid was dropped; in until the solution wasstrongly acid. Then without separating the benzene layer as in theprevious two examples, 500 cc. of acetic acid and 800 grams of zinc dustwere added. The mixture was stirred for 16 hours at 25 C-., thenrefluxed while stirring for four hours. The benzene layer was separatedand stirred together with 500 cc. of concentrated hydrochloric acid forone hour. The acid layer was removed and the benzene layer was: washedtwice with water and concentrated under vacuum. The residue was taken upin ether and the thiolactone was permitted to crystallize. Thev yield ofthe thiolactone obtained was 32 per cent of theory.

Examp e 4 500 cc. of ethyl alcohol, 200 grams of the cycloacetate, 500cc. of water and 300 grams of sodium hydrosulfide were placed in areaction vessel in the order named, and stirred for two hours at 25 C.,then for 6' hours at refluxtemperature. The reaction mixture was cooledto 25 by allowing to stand for 16 hours. 1600. cc. of benzene were addedand 350 cc. of concentrated hydrochloric acid were dropped in from aseparatory funnel. When the. reaction mixture was strongly acidified,the aqueous layer turned white in color, while the benzene layer was adeep yellow. The benzene layer. was separated, washed with water andconcentrated under vacuum to a syrup.

The syrupy product was taken up in 1400 cc. of glacial acetic acid. 500grams. of powdered zinc were then added and the mixture stirred for 16hours at 25 C., and then refluxed for two hours. The zinc was filteredoff, washed with acetic. acidand finally with benzene. The filtrateswere/combined and distilled to a syrup under vacuum. The syrup was takenup in 500 cc. of benzene. There were then added 400 cc. of hydrochloric.acid, while stirring for 3.0 minutes. The mixture was stirred for anadditional 30 minutes and the benzene layer was separated, washed withwater. and distilled under vacuo to give a white crystalline residue.This. was. taken up inether, cooled for 4 hours-ate G. andfiltered. The.amount of, 3;,4- (1,3-dibenzyle2-keto-imida- Example 5 'In a reactionvessel provided with stirrer and condenser, there were placed 1500 cc.of ethyl alcohol and. 500 grams of the cycloacetate. This mixture, wasstirred for 30 minutes in order to break up all the lumps of thecycloacetate. 1000 cc. of waterand 750 grams of sodium hydrosulfidewerethenadded in the order named. The mixture was stirred for two hoursat C. and finally for 6 hours at reflux temperature, then allowed tocoolv for 16 hours. To the reaction -mixture were added 2,000 cc. ofbenzene,.and concentrated hydrochloric acid were then slowly added whilestirring until the solution was strongly acid. A totalof850 cc. of theacid was added.

The aqueous layer was siphoned oil and discarded. To the benzenesolution there were added 2,000 cc. of water, 250 grams of zinc dust and685 cc. of concentrated hydrochloric acid. The reaction mixture wasstirred for 2%, hours at 40 C. The temperature was thenheld at 50 C. for1 /2 hours and finally for one hour at 60 C.- It was then allowed tocool to 25 C. The benzene layer was separated and washed twice with 500cc. of water. It was then concentrated to a syrup under vacuum, taken upin ether, and cooled to 25 C. The 'thiolactone was obtained in yield ofapproximately 63 per cent of theory.

The procedure in this example eliminates a concentration step of thebenzene solution prior to the reduction step, thereby further shorteningthe process. 7 I

Example 6 "1500 cc. of alcohol, 500 grams of the cycloacetate, 1,000 cc.of water and 500 grams of so-" dium hydrosulfide were placed in theorder named in a reaction vessel and stirred for 2 hours at about 25 C.The mixture was then stirred at reflux for six hours, after which it wasallowed to cool to about 25 C. 2,000 cc. of benzene were added and about500 cc. of concentrated hydrochloric acid dropped in gradually whilestirring.

The aqueous layer was siphoned off and discarded.

To the remaining oily layer, there were added 2,000 cc. of water, 250grams of zinc dust and 685 cc. of concentrated hydrochloric acid.. Themixture was then stirred for 2 hours at 40 C., 1 hour at 50 C. and for1, hour at 60 C. The benzene layer was separated, washed twice with 500cc. of water and concentrated to a syrup under vacuum. The whitecrystalline residue was taken up and cooled for 4 hours at about 4 C.and filtered. The thiolactone was obtained in the yield of 63 per centof theory.

Instead of employing the cycloacetate in the above examples, there canalso be employed the small portions (within 1 hours) 1.6 liters of a3.75 molar solution of phosgene in xylene (=6 6 moles COClz) and 2.7liters 6 N potassium hydroxide (=14moles). The mixture is then acidifiedwith concentrated hydrochloric acid, and the precipitate is then washedthoroughly with hot alcohol, and the aqueous filtrate is extractedseveral times with ethyl acetate. The alcoholic solution and the ethylacetate extract contain all the imidazolidone-dicarboxylic acid formed.The alcohol insoluble part of the precipitate is pure starting material.The alcoholic and ethyl acetate solutions are taken to dryness. and theresidue is refluxed with benzene until it becomes completelycrystalline. The cooled mixture is filtered; the main part of thedibenzyl-imidazolidone-dicarboxylic acid remains on the funnel. It canbe recrystallized from ethyl acetate forming prisms, melting first at167 C., then resolidifying again and melting at 236 C.

The benzene mother liquor is concentrated in vacuo, and the rest of thereaction product is isolated in the form of its anhydride in the fol-,

lowing way: The oily, residue is refluxed with acetic anhydride, thenthe mixture is concentrated and benzene is added. The anhydride formedcrystallizes in nice needles melting at 236-237" C.

A mixture of grams of the anhydride of 1,3 dibenzyl imidazolidone (2')-cis-4,5-dicarboxylic acid, grams of zinc dust, 100 grams zinc powder(40 mesh), 1500 cc. acetic anhydride and 500 cc. acetic acid is stirredand refluxed for 10-15 hours. The dicarboxylic acid can be used in teadof the anhydride. In that case, the acid is first mixed with the aceticanhydride, refluxed for 10 minutes and then the other constituents areadded. The amounts of acetic acid and anhydride can be reduced to aboutwithout affecting the yield. If too little is used, the yield isreduced. After that time, the mixture is cooled, filtered and theprecipitate on the funnel washed with ethyl acetate. The filtrate isconcentrated in vacuo, and the oily or partly crystalline residue istreated with ice water and ethyl acetate, until all the organicsubstance is dissolved. The ethyl acetate layer is washed with water,dried with sodium sulfate and concentrated in vacuo. The oily or partlycrystalline residue is boiled up. with acetic anhydride, in order toreconvert any of the compound decomposed during the treatment with waterinto the cyclic acetate. The mixture is again concentrated in vacuo.Xylene is then added to the residue, and part of it is distilled off invacuo, then ether and petrol-ether are added. The reaction productseparates in fine needles or prisms which melt at 103-104 C. Afterdrying, the melting point is 124-125 C.

1,3 dibenzyl-cis-4-carbory-5-formyl-imidazolidone-Z-or its cyclic form3,4-(1',3'-dibenzyl- 2' -keto-imidazolido) -2-ke.to-5-.hydro$y-tetrahydrofuran An excess of 3 N sodium hydroxide solution isadded to a solution of the acetate of the cyclic form of 1,3 dibenzylcis-4-carboxy-5-formylimidazolidone-2 in dioxane. After 2 minutes themixture is acidified with dilute sulfuric acid and extracted with ether.The ether extract is washed, dried with sodium sulfate, and concentratedin vacuo. The residue is recrystallized from a mixture of acetone, etherand petrolether.

The compound crystallizes in colorless needles or prisms melting at109-110 C.

Instead of employing the 3,4-(1,3-dibenzy1- 7 2 keto -imidazolido)-2-keto -'5 -acetoxy--"tetrahydrofuran, the correspondingSA-(LS-di-p-methoxybenzyl 2'--keto-imidazolido)-2'-keto-5-acetoxy-tetrahydrofuran may be employed as starting material,in which case the corresponding thiolactones are obtained.' It will beunderstood that instead of the 5-acetoxy-tetrahydrofuran, thecorresponding analogous lower aliphatic acid derivatives can also beemployed, as for example, the propionate or the butyrate. These acylderivatives can be prepared in the same way as the acetate; namely, bycarrying out the reduction of the anhydride of the1,3-disubstitutedimidazolidone-(Z) -cis-4,5-dicarboxylic acid with zincin the presence of the corresponding lower aliphatic acid and itsanhydride.

The 1,3 di p methoxybenzyl-intermediates can be prepared in thefollowing manner as described in the Goldberg and Sternbachapplications.

Cyclic acetate of'1,3-di-1o-methoxybenzyZ-cis-4-0117130131]-5-JOTmlIZ-imidd20lid0n6-2 3,4 (1,3di-p-vfiethorybenzyZ-Z'keto-imidazo- Zido)-2-7ceto-5-acetoxy-tetrahydrofumn 112 grams of-1,3-di-p-methoxybenzyl-imidazolidone-(2)-ois-4,5-dicarboxy1ic acid arerefluxed forlO minutes with 840 cc. of acetic anhydride. Theclearsolution is cooled slightly; 325 grams of zinc dust and 330 cc. aceticacid are added, and the reaction mixture is stirred and refluxed for 16hours. After cooling, ethyl acetate is added and the zinc and zincacetate is extracted 3 times with boiling ethyl acetate. The combinedethyl acetate washings and filtrates are concentrated in vacuo, and theresidual oil is treated with benzene. After allowing the solution tostand for a few hours at room temperature, zinc acetate and unchangedstarting material are separated by decantation. After distilling ofi thebenzene in vacuo, the residue crystallizes upon treatment with ether andpetrol-ether. M. P. 80-93 C. After two recrystallizations fromacetone-ether, the melting point is 110-111 C.

Alternatively, the anhydride of the dicarboxylic acid can be reducedwith zinc in .a mixture of acetic acid and acetic anhydride to form thecyclic acetate.

1,3 di 'p-.methoxybenzyl-imidazolidone- (2) cis-4,5-dicarboxylic acidcan be prepared by reacting meso-dibromo-succinic acid withp-methoxybenzyl-amine to form meso-bis-p-methoxybenzylamino-succinicacid, and condensing the latter with phosgene.

We claim:

1. A process for producing 3,4-(l' 3-diara1kyl- 2'-keto-imidazolid0) 2keto-thiophanes which consists in reacting a compound from the groupconsisting of a 3,4-(1Q3-diaralkyl-2keto-imidazolido) -.2-keto-5-acyloxytetrahydrofuran, 1,3- diaralkyl-cis-4-carboxy-5-formyl-imidazolidone- 2and its cyclic form, 3,4(l",3-diaralkyl-2'-ketoimidazolido)-2-keto-5-hydroxy tetrahydrofuran with an alkali metal hydrosulfide inan aqueous medium, and reducing the reaction product with nascenthydrogen.

2. A process as in claim 1 in which an aqueousalcoholic medium isemployed.

3. A process as in claim 1 in which the reaction product is treated withzinc in the presence of hydrochloric acid to liberate nascent hydrogen.

4. A process as in claim 1 wherein diaralkyl is dibenzyl.

5. Aprocess as in .claim 1 in which the alkali metal hydrosulfide issodium hydrosulfide.

6. A process as in claim 1 in which sodium hydrosulfide in anapproximately mixture of Water and alcohol is employed.

7. A process for producing 3,4-(1',3dibenzyl- 2'-keto imidazolido)2-keto-thiophane which consists in reacting3,4-(l',3'-dibenZyl-2'-ketoimidazolido) 2-keto-5-acetoxy-tetrahydrofuranwith sodium hydrosulfide in an approximately 50% mixture of water andethyl alcohol by refluxing the mixture and reducing the reaction productwith zinc in the presence of hydrochloric acid.

8. A process for producing .3,4-(l',3 -dibenzyl- 2' keto imidazolido)2-ketothiophane which consists in reacting3,4-(123-dibenzyl-2'-ketoimidazolido) 2-keto-5-acetoxy-tetrahydrofuranwith sodium hydrosulfide in an approximately 50% mixture of water andethyl alcohol by refluxing the mixture and reducing the reaction productwith Zinc in the presence of acetic acid.

JOSEPH DONALD SURMATIS. WALTER KIMEL.

No references cited.

1. A PROCESS FOR PRODUCING 3,4-(1'',3''-DIARALKYL2''-KETO-IMIDAZOLIDO) -2 - KETO-THIOPHANES WHICH CONSISTS IN REACTING A COMPOUND FROM THE GROUPCONSISTING OF A3,4-(1'',3''-DIARALKYL-2''KETO-IMIDAZOLIDO)-2-KETO-5-ACYLOXY -TETRAHYDROFURAN, 1,3DIARALKYL-CIS-4-CARBOXY-5-FORMYL-IMIDAZOLIDAONE2 ANDITS CYCLIC FORM,3,4-(1'',3''-DIARALKYL-2''-KETOIMIDAZOLIDA)-2-KETO-5-HYDROXY-TETRAHYDROFURANWITH AN ALKALI METAL HYDROSULFIDE IN AN AQUEOUS MEDIUM, AND REDUCING THEREACTION PRODUCT WITH NASCENT HYDROGEN.